Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
  • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
  • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Definitions

• This invention relates to polysaccharides grafted with antioxidants, and preferably hyaluronic acid or crosslinked hyaluronic acid grafted with hindered phenols.
• the synovial fluid found in mammalian joints functions as a lubricant and shock absorber.
• the most important component of the synovial fluid is sodium hyaluronate, which makes the greatest contribution to the mechanical properties of the fluid.
• Hyaluronic acid is a naturally occurring high molecular weight glycosaminoglycan having a repeating disaccharide unit of 2-amino-2-deoxy-3- O -( ⁇ -D-glucopyranosyluronic acid)- D -glucose.
• the disaccharides are joined to form an unbranched, uncrosslinked polysaccharide chain by ⁇ 1 ⁇ 4 glucosidic bonds.
• hyaluronic acid occurs in cell coats, pericellular gels, the extracellular matrix substance of connective tissues of vertebrates, the vitreous humor of the eye, human umbilical cord tissue, rooster combs and in some bacteria.
• Hydroxyl radicals come from two sources.
• the primary source is white blood cells which enter the joints when they are inflamed, and release xanthine peroxidase and other enzymes to form superoxide anion, hydrogen peroxide and hypochlorite, which upon breakdown form hydroxyl radical.
• Another source for hydroxyl radical is the reduction of oxygen by reducing agents in the presence of iron.
• a common reducing agent in the body is ascorbic acid. Oxygen is reduced by iron(I I) to form superoxide anion, which then reacts with iron (III) to form hydrogen peroxide. Hydrogen peroxide is reduced to hydroxyl radical.
• This invention relates to novel ways of increasing the resistance of polysaccharides, in particular hyaluronic acid and sodium hyaluronate, to hydroxyl radicals by grafting them with antioxidants.
• This invention pertains to grafted polysaccharide compositions comprising polysaccharide grafted with antioxidant on at least one hydroxyl group of the polysaccharide as defined in claim 1.
• the polysaccharide comprises polysaccharide containing acidic groups.
• the polysaccharide comprises hyaluronic acid or a salt of hyaluronic acid; the antioxidant comprises hindered phenol; and the grafted composition has substantially greater resistance to hydroxyl radicals than does un-grafted hyaluronic acid or its sodium salt.
• the invention also pertains to pharmaceutical compositions for treating inflammation of mammalian joints, e.g., arthritis, for preventing post-operative adhesion formation and for promoting the healing of chronic wounds, comprising as the active component the antioxidant grafted polysaccharide of this invention.
• the invention pertains to drug delivery systems comprising antioxidant grafted polysaccharide which has been crosslinked.
• the invention also pertains to cosmetic compositions comprising the grafted polysaccharide of this invention.
• the invention pertains to methods for treating inflammation of mammalian joints, e.g. arthritis, reducing the incidence of post-operative adhesion formation and promoting the healing of chronic wounds and ulcers comprising injecting or applying an effective amount of a pharmaceutical composition comprising as the active component antioxidant grafted polysaccharide of this invention.
• compositions of this invention comprise material having a formula selected from the group consisting of: and wherein R represents the backbone of polysaccharide or crosslinked polysaccharide containing acidic groups or salts thereof, -(O)- is the residue of a polysaccharide hydroxyl group, R 1 is hydrogen, C 1 -C 20 alkyl, phenyl or substituted phenyl, R 2 is C 1 -C 20 alkyl, phenyl or substituted phenyl, and Ar is aryl or substituted aryl.
• compositions of this invention comprise material having a formula selected from the group consisting of: and wherein R represents the backbone of polysaccharide or crosslinked polysaccharide containing acidic groups or salts thereof, -(O)- is the residue of a polysaccharide hydroxyl group; R 1 is hydrogen, C 1 -C 20 alkyl, phenyl or substituted phenyl; and R 2 is C 1 -C 20 alkyl, phenyl or substituted phenyl.
• R 1 is selected from the group consisting of hydrogen, methyl, ethyl, i-propyl and t-butyl
• R 2 is selected from the group consisting of methyl, ethyl, i-propyl and t-butyl.
• compositions comprise material of formulas I, II and IV wherein R 1 and R 2 are t-butyl, and wherein the polysaccharide comprises hyaluronic acid.
• the polysaccharides for use in this invention containing acidic group include, members selected from the group consisting of hyaluronic acid, chondroitin sulfate, keratan sulfate, dermatan sulfate, heparan sulfate, heparin, carboxymethyl cellulose, hydroxyethylcarboxymethyl cellulose, carboxymethyl starch, pectin, xanthan, alginic acid, polygalacturonic acid, polymannuronic acid, polyglucuronic acid and carrageenan. The most preferred is hyaluronic acid.
• the preferred salts in accordance with this invention comprise salts of an alkali or alkaline earth metal, aluminum or ammonium.
• the most preferred salt is a salt of sodium.
• the grafted polysaccharides of this invention may also be crosslinked.
• Crosslinked polysaccharides may be prepared by any methods disclosed in the art.
• Sakurai et al. in U.S. Patent No. 4,716,224 disclose crosslinked hyaluronic acid or salts thereof prepared by crosslinking hyaluronic acid or its salts with a polyfunctional epoxide.
• Sakurai et al. disclose crosslinked glycosaminoglycan or salts thereof, prepared by crosslinking a glycosaminoglycan or a salt thereof with a polyfunctional epoxy compound.
• 0 507 604 A2 disclose ionically crosslinked carboxyl-containing polysaccharides where the crosslinking agent is a compound possessing a trivalent cation.
• Gurlson et al. in U.S. Patent No. 4,716,154 disclose crosslinking hyaluronic acid with bi- or polyfunctional epoxides or their corresponding halohydrins, epihalohydrins or halides, and divinyl sulfone.
• Gurlson et al., in U.S. Patent No. 4,772,419 also disclose crosslinking hyaluronic acid with polyfunctional epoxides.
• Balazs et al. disclose chemically modifying hyaluronic acid by reaction with aldehydes such as formaldehyde, glutaraldehyde and glyoxal, and teach the possibility that crosslinking has occurred.
• aldehydes such as formaldehyde, glutaraldehyde and glyoxal
• crosslinking hyaluronic acid by reaction with biscarbodiimides.
• a preferred method for crosslinking polysaccharides is by their reaction with carboxylic acid di- or polyanhydrides.
• a preferrred crosslinked composition comprises material of above formula I where R 1 and R 2 are t-butyl, and the polysaccharide is hyaluronic acid or its sodium salt crosslinked by reaction with pyromellitic dianhydride.
• the grafting level is most readily expressed in terms of the number of equivalents of antioxidant that are present per equivalent of polysaccharide repeating unit.
• the minimum level of grafting could be as low as about 1 equivalent of antioxidant per 1000 equivalents of polysaccharide repeating units.
• a preferred minimum level is about 1 equivalent per 700, and the most preferred minimum level about 1 equivalent per 600 polysaccharide repeating units.
• the maximum level of grafting could be as high as about 1 equivalent per 10 equivalents of polysaccharide repeating units.
• a preferred maximum level is about 1 equivalent per 100, and the most preferred maximum level about 1 equivalent per 400 polysaccharide repeating units.
• the antioxidant grafted composition in accordance with this invention is derived from hyaluronic acid or its salts, it has substantially greater resistance to degradation caused by hydroxyl radical than does un-grafted hyaluronic acid or its salts.
• the antioxidant grafted compositions are prepared by reaction of polysaccharides with hydroxyl-reactive antioxidant derivatives.
• hydroxyl-reactive antioxidant derivative is intended to mean an antioxidant containing a functional group capable of reacting with hydroxyl groups contained in a polysaccharide.
• the preferred hydroxyl-reactive antioxidants for preparing the compositions of this invention are selected from the group consisting of: and wherein R 1 is hydrogen, C 1 -C 20 alkyl, phenyl or substituted phenyl; R 2 is C 1 -C 20 alkyl, phenyl or substituted phenyl; A is -C(O)X, -C(O)OCH 2 CH 2 OCH 2 CH 2 Y, -C(O)NHCH 2 CH 2 CH 2 Y, -OCH 2 CH 2 OCH 2 CH 2 Y or -CH 2 Y; B is -C(O)X, -CH 2 Y, or X; X is halogen, 1-imidazole, phenoxy, nitrophenoxy, p-toluenesulfonate, methanesulfonate or alkyl or aryl carboxylate; Y is halogen, p-toluenesulfonate and methanesulf
• the preferred hydroxyl-reactive antioxidants comprise hydroxyl-reactive hindered phenols of structure XII where R 1 is hydrogen, methyl, ethyl, i-propyl or t-butyl, and R 2 is methyl, ethyl, i-propyl or t-butyl.
• hindered phenol refers to phenols having at least one position ortho to the hydroxyl group occupied by phenyl, substituted phenyl or C 1 -C 20 alkyl substituent.
• Preferred hydroxyl-reactive hindered phenols of structure XII comprise those wherein R 1 and R 2 are t-butyl, A is -C(O)X, -CH 2 Y or -C(O)OCH 2 CH 2 OCH 2 CH 2 Y, where X is chlorine or 1-imidazole and Y is bromine.
• preferred hydroxyl-reactive hindered phenols are 3,5-di-t-butyl-4-hydroxybenzoyl chloride, 2,6-di-t-butyl-4-bromomethylphenol, 3,5-di-t-butyl-4-hydroxybenzoyl 2-[2-(chloroethoxy)ethoxy]ethyl ester and 3,5-di-t-butyl-4-hydroxybenzoyl-1-imidazole.
• hydroxyl-reactive antioxidant derivatives may readily react with water, it is preferred that their reaction with polysaccharide be carried out in a dry, polar, aprotic solvent.
• Preferred solvents are N-methyl pyrrolidinone, N-ethyl pyrrolidinone, N-cyclohexyl pyrrolidinone, 4-methyl morpholine N-oxide, dimethyl formamide, sulfolane and dimethyl sulfoxide.
• Salts of acidic polysaccharides may not be soluble in the preferred solvents.
• the sodium salt of hyaluronic acid is not soluble in the preferred solvents, and so it is generally convenient for the purpose of this embodiment to convert the sodium salt to a tetraalkyl ammonium salt to increase solubility. After the grafting reaction of tetraalkyl ammonium salt and hydroxyl-reactive antioxidant derivative, the product can be converted back to the sodium form by ion exchange.
• the crosslinking reaction can be carried out either before or after the grafting reaction. It may also be carried out simultaneously with the grafting reaction in those cases where the solvents used for crosslinking are the same as those used for the grafting reaction.
• the ratio of hydroxyl-reactive antioxidant derivative to polysaccharide is most readily expressed in terms of the moles of antioxidant derivative utilized per equivalent of repeating unit in the polysaccharide.
• the minimum level of hydroxyl-reactive antioxidant derivative could be as low as about 1 equivalent per 1000 equivalents of polysaccharide repeating units.
• a preferred minimum level is about 1 equivalent per 700, and the most preferred minimum level about 1 equivalent per 600 polysaccharide repeating units.
• the maximum level of hydroxyl-reactive antioxidant derivative could be as high as about 1 equivalent per 10 equivalents of polysaccharide repeating units.
• a preferred maximum level is about 1 equivalent per 100, and the most preferred maximum level about 1 equivalent per 400 polysaccharide repeating units.
• the invention pertains to compositions for treating inflamed mammalian joints, e.g., arthritis, for preventing post-operative adhesions and for promoting the healing of chronic wounds and ulcers.
• the active component of these compositions comprises the antioxidant grafted polysaccharides of this invention.
• the preferred antioxidant grafted polysaccharides are hindered-phenol grafted hyaluronic acid or hindered-phenol grafted crosslinked hyaluronic acid, or pharmaceutically acceptable salts thereof.
• Pharmaceutically acceptable salts include salts of an alkali or alkaline earth metal, aluminum or ammonium.
• the preferred pharmaceutically acceptable salt is sodium.
• the antioxidant grafted polysaccharide compositions of this invention can be used to prevent post-operative adhesions in any animal that is susceptible to unwanted adhesion formation following surgery.
• the compositions are used to prevent adhesions from developing in mammals, preferably human beings. They are useful in all types of surgery where it is desired to inhibit the formation of post-surgical adhesions, e.g., abdominal surgery, gynecological surgery, thoracic surgery, orthopedic surgery, neurological surgery and ophthalmological surgery.
• the preferred compositions for this use are hindered-phenol grafted hyaluronic acid or hindered-phenol grafted crosslinked hyaluronic acid, or pharmaceutically acceptable salts thereof.
• Adhesion preventatives may be administered to the site of surgical trauma by any convenient mode such as, for example, by lavage, by coating directly on the site in a gel, cream, film or foam, or by any other convenient method.
• the administration of adhesion preventatives can occur at any time before significant wound healing has occurred. It is preferred to administer it at the conclusion of surgery, just prior to closing of the wound. However, in some cases it may be desirable to administer the preventative continually over a period of time.
• An effective amount of adhesion preventative is an amount necessary to affect a reduction in the incidence of post-operative surgical adhesions. Preferably, the amount should be enough to coat the entire area exposed to the surgical trauma, and desired an additional amount sufficient to coat body tissue adjacent to the area of trauma.
• the antioxidant grafted polysaccharide compositions of this invention can also be used to promote the healing of chronic wounds, e.g. burns, and ulcers, e.g. diabetes foot ulcers in mammals, in particular, human beings.
• the preferred compositions for this use are hindered-phenol grafted hyaluronic acid or hindered-phenol grafted crosslinked hyaluronic acid, or pharmaceutically acceptable salts thereof.
• Hyaluronic acid retains moisture and also has angiogenesis characteristics that make it useful for this application.
• the compositions may be used alone in aqueous solution, preferably physiological saline solution, or the solutions may be combined with wound healing drugs and other water soluble polymers.
• a typical antioxidant grafted polysaccharide may contain as other ingredients water-soluble polymers, antibiotics, immunosuppressants and pain reducers.
• the hyaluronic acid derivative is usually dissolved in physiological saline to a sufficient viscosity to pass through an injection needle.
• the maximum viscosity is about 50,000 cps, preferably about 30,000 cps.
• the minimum viscosity is about 5,000 cps.
• a typical knee joint synovial fluid supplementation injection procedure is similar to one described by Miller et al. in J. Bone and Joint Surgery, 40 , p.636 (1985).
• a sterile solution 2.5 ml, of the sodium salt of antioxidant grafted hyaluronic acid (concentration of grafted hyaluronic acid: 10 mg/ml) in buffered saline (sodium chloride 8.5 mg/ml, dibasic sodium phosphate 0.537 mg/ml, sodium dihydrogen phosphate 0.016 mg/ml) is slowly drawn into a syringe to ensure the absence of air pockets.
• the knee is then prepared for injection by cleaning with soap, wiping with cetyl trimethylammonium bromide and painting with tincture of iodine.
• the solution is injected into a synovium cavity through a premarked triangular arc at the lateral side of the joint bound by the tibial plateau, the edge of the ligamentum patellae, and the curve of the lateral femoral condyle.
• Local anaesthesia may be used prior to injection.
• knee aspiration with the buffered saline solution may be needed prior to the synovial fluid supplementation injection.
• Such a procedure is described by Dahlberg et al. in Arthritis & Rheumatism, 37 , 1994, page 521.
• the injectable solution may contain materials in addition to the grafted composition. These include water soluble polymers such as chondroitin sulfate, dermatan sulfate, and/or a phospholipid to improve the lubricity of the solution. Anesthetics, anti-inflammatory reagents, antibiotics, antibacterials, cytotoxins and sugars may be added also.
• Antioxidant grafted polysaccharides of this invention particularly in the crosslinked form may be used as a drug delivery system.
• the preferred compositions for this use are hindered-phenol grafted hyaluronic acid or hindered-phenol grafted crosslinked hyaluronic acid, or pharmaceutically acceptable salts thereof.
• Crosslinked hyaluronic acid forms a molecular cage in which molecules with pharmacological activity can be dispersed. The substances contained in the cage are delivered into the environment by diffusion.
• the drug molecule, or mixture of drug molecules may be covalently or non-covalently bonded to the hyaluronic acid.
• the covalent bonding can be via attachment to the carboxylic acid or hydroxyl groups of the hyaluronic acid moieties.
• the gels, films, threads, particles or sponges of hyaluronic acid-based composition may be placed, sprayed, ingested, injected or implanted at the location where the contained pharmacological substance is needed.
• These substances may be therapeutic drugs (such as anesthetics, analgesics, anti-inflammatories, diuretics, antagonists, antibiotics, hormones, antirheumatics, adrenergic agonists, cytostatics, antihypertensives or immunosuppressant agents), growth factors, enzymes or cellular anti-adhesion compounds.
• Antioxidant grafted polysaccharides of this invention can also function as components of cosmetics for topical uses.
• the preferred compositions for this use are hindered-phenol grafted hyaluronic acid or hindered-phenol grafted crosslinked hyaluronic acid, or pharmaceutically acceptable salts thereof. Because hyaluronic acid has been shown to hold moisture under low relative humidity conditions and yield a pleasant and smooth feeling at high relative humidities, it has been used as a moisturizer in cosmetic formulations.
• the compositions of this invention will provide similar effects. Mixtures of the grafted hyaluronic acid compositions with other low cost water-soluble polymers such as carboxymethyl cellulose, pectin, alginate, soy protein, casein and gelatin may also be employed.
• Natural extracts of plant sources such as cactus aloe vera, mesquite, matricaria chamomilla, tumeric, carrot, jojoba, rose and others, may be blended into a cosmetic formulation containing grafted hyaluronic acid.
• Alpha hydroxy acids such as lactic and hydroxyethanoic may be added to the formulation to improve the plasticity of the skin.
• a typical anti-aging cosmetic composition is: 2-hydroxyethanoic acid, 7%, propylene glycol, 15%, hindered-phenol grafted hyaluronic acid solution (1 g/100 ml), 1%, water, 60% and ethyl alcohol, 17%, where all percentages are by weight.
• a formulation for facial soft gel is: aqueous slurry of carboxymethyl cellulose (3 g/100 ml), 25%, aqueous solution of triethanolamine (10 g/100 ml), 11%, Methyl Gluceth-10, 5%, hindered-phenol grafted hyaluronic acid aqueous solution (1 g/100 ml), 1%, perfume and preservatives, 1%, water, 57%, where all percentages are be weight.
• a typical essential skin moisturizer composition is hydroxyethyl cellulose, 0.5%, Methyl Gluceth-10, 2%, glycerin, 2%, hindered-phenol grafted hyaluronic acid aqueous solution (1 g/100 ml), 1%, water, 94%, preservatives and perfume, 0.5%, where all percentages are by weight.
• Example 1 To a solution of 10 g of the methyltricaprylammonium salt of hyaluronic acid (prepared by the method of Example 5) in 1000 ml of dry N-methylpyrrolidinone (NMP), 0.4 g of 3,5-di-t-butyl-4-hydroxybenzoyl chloride (Example 1) was added. The mixture was tumbled for 3 hours and then stored at 10°C for 16 hours. For ion exchange back to the sodium salt, an aqueous solution of NaCl (15 g in 250 ml of water) was then added to the reaction mixture. After the resulting solution had been stirred for 1 hour, 3 g of sodium bicarbonate and 200 ml of acetone were added to precipitate the product.
• NMP dry N-methylpyrrolidinone
• the polymer was filtered and washed five times with acetone/water (ratio: 4/1, 200 ml) and then with 100 ml of acetone.
• the product was further purified by redissolving it in 1 l of water and then precipitating it into a large volume of methanol. Four grams of product was obtained.
• Example 4 To a solution of 2 g of the methyltricaprylammonium salt of hyaluronic acid (prepared by the method of Example 5) in 280 ml of NMP was added 0.25 g of 3,5-di-t-butyl-4-hydroxybenzoyl-1-imidazole (Example 4). The mixture was maintained at 45°C for 20 hours, and then it was ion exchanged back to the sodium salt form as described in Example 6. The product weighed 0.92 g.
• the crosslinking reaction was carried out first, by mixing 2 g of the methyltricaprylammon ium salt of hyaluronic acid (prepared by the method of Example 5), 0.2 g of diglycidyl ether of bisphenol A, and 280 ml of NMP, and maintaining the mixture at 45°C for 24 hours. To this mixture was then added 0.2 g of 3,5-di-t-butyl-4-hydroxybenzoyl chloride, and then the entire reaction mixture was maintained at room temperature for 17 hours. The product was converted to the sodium salt and worked up as described for Example 6.
• Hydroxyl radicals were generated by the reaction of ferric ion with ascorbic acid as described by Wong et al. Inorganic Biochemistry, 14 , p. 127 (1981).

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